Oral hypoglycemic agents such as tolbutamide have been widely used to treat diabetes-induced hyperglycemia. However, the use of these agents has been challenged by investigators who find an increased risk of cardiovascular deaths in patients treated with the sulfonylurea. By contrast, our studies suggest that tolbutamide protects the ischemic heart, possibly by stimulating ATP generation by glycolysis and reducing coronary resistance. The metabolic effects of tolbutamide on both the normal and ischemic heart remain the central focus of this investigation. We will examine the mechanism underlying the stimulation glycolysis in the normal and ischemic myocardium. We shall also explore the basis for alterations in the malate-aspartate shuttle.